Adenosine receptors and phosphodiesterase inhibitors stimulate Cl- secretion in Calu-3 cells

We investigated cystic fibrosis transmembrane conductance regulator (CFTR) activation by clinically used phosphodiesterase inhibitors (PDEis) in Calu-3 cell monolayers alone and in combination with A(2B) adenosine receptor stimulation. This receptor pathway has previously been shown to activate wild-type and mutant CFTR molecules. Several PDEis, including milrinone, cilostazol (Pletal), papaverine, rolipram, and sildenafil (Viagra), produced a short circuit current (I-sc) that was glibenclamide-sensitive, achieving 20-85% of forskolin-stimulated I-sc Papaverine, cilostazol, and rolipram also augmented both the magnitude and the duration of I-sc following low dose stimulation of adenosine receptors with Ado (0.1-1.0 muM, P < 0.01). Subsequent studies demonstrated that very low concentrations of cilostazol or papaverine (similar to 1/2 peak serum concentrations) were sufficient to activate I-sc and both agents markedly augmented Ado-stimulated (1 muM, P < 0.01). Our results provide evidence that select PDEis, at concentrations achieved as part of systemic therapies, can activate CFTR-dependent I-sc in Calu-3 cell monolayers. These studies also indicate that PDEis have the capacity to augment an endogenous CFTR-activating pathway in an in vivo-like model system, and supports future investigations of these agents relevant to cystic fibrosis.